Date of Award

11-2016

Document Type

Thesis

Degree Name

Master of Science in Medical Sciences (MSMS)

Department

Medical Education

First Advisor

Dr. Rajesh Mohanraj

Second Advisor

Ernest Adeghate

Third Advisor

Dr. Gautam Sethi

Abstract

Cisplatin (CSP) is a potent and widely used chemotherapeutic agent. However, clinical efficacy of CSP is compromised due to the elicitation of nephrotoxicity and ototoxicity. In this study, I have investigated the nephroprotective effects of a phytochemical – genipin (GP) isolated from gardenia flower (Gardenia jasminoides), on a murine model of cisplatin-induced nephropathy. CSP-induced renal tissue injury was characterized by elevated levels of serum blood urea nitrogen (BUN), creatinine (Cr) and cystatin-C. In addition, levels of kidney injury molecule-1 (KIM-1) were increased in the renal tissues of CSP administered animals. CSP also induced renal oxidative stress, evidenced by increased NADPH oxidase, and diminished superoxide dismutase (SOD) activities. Furthermore, elevated levels of renal 4- hydroxynonenal (4-HNE) and 3-nitrotyrosine (3-NY) and diminished glutathione (GSH) levels signified profound oxidative stress in CSP administered animals. Renal inflammation was exaggerated in CSP treated animals, which was revealed by elevated levels of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL1-β). Increased activation of mitogen activated protein kinases (MAPKs) was observed in CSP administered animals. Finally, CSP also induced apoptosis in the renal tissues, revealed by increases in caspase-3/7 and poly (ADP-ribose) polymerase [PARP] activities, DNA fragmentation, and terminal deoxynucleotidyl transferees’ dUTP nick-end labeling (TUNEL) staining in the kidney sections. Interestingly, GP treatment markedly attenuated the cisplatin- induced oxidative/nitrative stress, inflammation, and cell death in the kidney, and improved renal function. Thus, results from this present suggest that GP may represent a promising new protective strategy against cisplatin-induced nephrotoxicity.

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